Inflammation is the foundation for cancer and degenerative/autoimmune diseases. Small changes in diet and exercise, e.g. omega-3 oils, vitamin D, low starch, and maintaining muscle mass, can dramatically alter predisposition to disease and aging, and minimize the negative impact of genetic risks. Based on my experience in biological research, I am trying to explain how the anti-inflammatory diet and lifestyle combat disease. 190 more articles at http://coolinginflammation.blogspot.com

Anti-Inflammatory Diet

All health care starts with diet. My recommendations for a healthy diet are here:

Friday, January 2, 2015

'Tis the season to discuss phytochemicals.Plants produce a vast array of organic chemicals starting from molecules produced by all organisms, including humans.Essentially all of these phytochemicals are potent adaptations to kill.Phytochemicals kill plant pathogens, bacteria and fungi, as well as insects.Thus, the natural, plant extracts that humans use for flavor enhancers (herbs, spices, and teas), fragrances, recreational/medicinal mind and attitude modifiers (alkaloids, psychopharmaceuticals, etc.), herbal medicines, etc. are present in plants, first and foremost, as antibiotics and insecticides.Humans have evolved to taste (bitter) and smell phytochemicals to avoid their toxicity, and have adapted culturally to exploit the impact of phytochemicals on body and mind.In this seasonal post, I focus on the terpenoids in Frankincense and Myrrh, to explore how plant biochemistry contributed to the gifts of the Magi.

It All Starts with Central Metabolism

Phytochemicals are complicated plant chemicals that are produced by a series of enzyme-controlled reactions (Central Metabolism) from the array of chemicals used by plants to convert photosynthetic carbohydrates (fructose and glucose) into the molecules (sugars, amino acids, fatty acids, nucleic acids) used to make the macromolecules of cells (polysaccharides, proteins, fats, DNA/RNA). Alkaloids and phenolics, e.g. phytoalexins, are made from amino acids (phenylalanine) and terpenoids are made from fatty acids (acetyl CoA/Mevalonate) or other intermediates in glycolysis. Thus, central metabolism that converts glucose/fructose into pyruvate and the acetyl CoA (see mevalonate pathway left) of mitochondrial fatty acid metabolism, is further converted into amino acids and plant secondary compounds, phytochemicals. I am going to talk mainly about terpenoids in Frankincense (triterpenoid Boswellic acids) and Myrrh, and many related molecules (steroids) also produced by humans.

The major thesis here is that carbon dioxide is converted by photosynthesis into either sugars used to build the cell wall polysaccharides (soluble fiber) or larger toxic defensive chemicals, e.g. phytoalexins, resins, essential oils or lignin. Phytoalexins, e.g. the natural antibiotic resveratrol in wine, are made from phenylalanine along the same biochemical pathway used to produce lignin. Glyphosate, the herbicide, kills by blocking this unique plant pathway. Essential oils and resins are another group of natural antibiotics produced by converting acetyl CoA into a five carbon unit, IPP, which is then linked into larger and larger (10, 15, 20 carbons) molecules, terpenoids, that can rearrange into multiple ring structures. Only the smallest chemicals in the series evaporate to provide identifiable smells, e.g. Frankincense and Myrrh, while larger forms, e.g. cholesterol or testosterone in animals, are odorless solids.

Acetyl CoA to IPP

IPP

For those who enjoy the beauty of biochemistry: The most abundant enzyme on earth is RibisCo (ribulose bisphosphate carboxylase), the plant enzyme that combines carbon dioxide from air with a five-carbon phosphorylated sugar, ribulose bisphosphate, to produce two, three-carbon intermediates of glycolysis that can be converted into glucose or into acetyl CoA, the starting chemical for fatty acids, the mitochondrial TCA cycle, or via mevalonic acid to isopentanyl pyrophosphate (IPP), the building block for terpenoid synthesis.

In brief: Photosynthesis uses the energy from sunlight to convert carbon dioxide into sugars (glucose and fructose). Those sugars can be converted into a five-carbon, molecular building block for terpenoids, IPP. IPP molecules can then be linked together to make increasingly longer chains and those chains can be ultimately twisted into rings to make resins in plants and steroids in humans.

Terpenoid synthesis begins with IPP, which has five carbons in a branched chain and has a pair of phosphates, pyrophosphate that provide the energy to form chains of 5, 10, 15, etc. In plants, molecules of each of the incremental lengths are produced together and additional enzymes in different species of plants result in mixtures of molecules with different rings and functional groups. The smaller molecules evaporate more readily, so that mixtures are extruded from damaged trees as oils and gradually form resins as the remaining larger molecules predominate and solidify.

Shark Livers and the Horn of Africa

IPP with five carbons, an isoprene, is used to make GPP with ten, a monoterpene. Common monoterpenes are geranol and limonene that make the characteristic odors of geraniums and lemons. Sesquiterpenoids (15 carbons made from three IPPs) include the fragrance of patchouli. Diterpenes, such as sweet steviol, have twenty carbons, which can be chemically twisted into the chemicals that predominate in Myrrh resin, the Balm of Gileade. The triterpenes with 30 carbons can be rearranged with five rings to form steroids, such as cholesterol in animals or Frankincense. Linear squalene, is the major component in shark liver oil and provides the same function as a swim bladder in a boney fish.

Essential Oils Are Mixtures of Distilled Terpenoid and Phenylpropanoid Phytoalexins

Boswellic Acid

Phytoalexins and terpenoids have evolved as plant defenses against bacteria, fungi and insects, and they are toxic, because they interact aggressively with proteins through their chemical ring structures that are hydrophobic. These ring structures make the smaller versions volatile and soluble in organic solvents. Many of these chemicals have properties similar to petroleum products and may be used as solvents themselves, e.g. paint strippers or thinner. Steam distillation of plants produces mixtures of phytoalexins and terpenoids commonly called essential oils, which contain the volatile components “essential” for the odor identity of a plant.

Statins Block Cholesterol Synthesis

Statins were identified among a group of fungal antibiotics for their ability to block an early enzyme (marked in the mevalonate pathway above) in the production of cholesterol. The toxic side effects of statins derive from wholesale disruption of all of the essential pathways (everything below the inhibited enzyme) that are related to cholesterol, such as blood heme A found in hemoglobin, and ubiquinone (CoQ) found in mitochondrial electron transport and needed to reduce oxidative stress and glucose intolerance. Thus, for these examples, statins would contribute to anemia and type II diabetes/metabolic syndrome. The side effects are not surprising, since statins are fungal antibiotics that target pathways common to bacteria and human mitochondria. It is also not surprising that statins have unpredictable impacts on gut flora and the immune system.

34 comments:

ChenShak
said...

Hi doc,

I actually have some questions regarding some of your other posts. I would appreciate an answer so much!

I have developed alopecia areata (which is going on for about 4 months now).I've checked my vitamin D which was low and started to supplement.I've also ordered three soil-based probiotics from Amazon (which are recomended here: http://freetheanimal.com/2013/12/resistant-primer-newbies.html)

However, I couldn't understand your stand on some topics:1. You mostly speak of 'clostridium butyricum', but are the other soil-based oraganisms beneficial to autoimmune disease (or they may have the opposite effect)?2. Will taking many soil-based strains simultaneously hinder the developement of 'clostridium butyricum' (becuase they feed on the same food) and maybe better be avoided?3. What about probiotics from fermented food such as (especially Kefir and Sauerkraut) - I understand that milk bacteria can't live in the gut for long, but is it beneficial still (for autoimmune disease)?4. Are all the other common bacteria which are considered probiotic - Lactobacillus and Bifidobacteria are beneficial for autoimmune disease?5. Are the ~1 million of 'clostridium butyricum' in 'Probiotics-3' sufficient (isn't it just a "drop in the sea")?

I figure that there isn't still comprehensive knowledge about everything, but if you could elucidate any of the above It'll be great.

By the way - you posts helped me a lot so far to understand the subject so thanks.

Hi! What are your thoughts on garlic supplements? I read only positive things about garlic supplements being antibacterial and antifungal but reading about the phytochemicals in this post and previous posts I'm confused. Do the benefits outweigh the negatives? Thanks for your posts!

I looked into the evidence base for the antimicrobial properties origanum compactum, mainly through this study: http://www.ncbi.nlm.nih.gov/pubmed/16010969 'Minimum inhibitory concentrations of herbal essential oils and monolaurin for gram-positive & gram-negative bacteria' in the journal of Molecular and cellular Biochemistry.

From it "The major components that confer the antibiotic properties are two phenols, carvacrol and thymol".

Do you have any thoughts on its efficacy or lack thereof? Safety?

Having used it for SIBO symptoms that have now gotten better 2-3 months after using it, I'm not comfortable attributing any supposedly positive effects to the essential oregano oil extract. For 1, i was also using Monolaurin (https://en.wikipedia.org/wiki/Monolaurin).

Hi Dr. Ayers, I've been reading your blog for years and thanks for another brilliant article!

I know this is off topic but I have an article request. Recently the internet has been abuzz about a study that used a mathematical model to show that around 2/3rds of cancer incidence is a result of random stem cell mutations. If this is true then why does the rate of cancer vary dramatically around the world? Shouldn't it be about the same everywhere? I'd love for someone with your intellectual horsepower to comment on this study. Thanks either way!

DNA/gene replication in stem cells is the source of mutations that produce cancer.

I have taught that DNA replication errors/mutation is the major source of cancer mutations for the last couple of decades. Environmental carcinogens are of little relative importance, but tissue-specific rates of stem cell divisions are central to cancer. Of course smoking, alcohol consumption, mycotoxins, e.g. in African peanuts, and sunshine, can increase replication rates of injured tissues and produce geographical increases in cancers of particular organs.

The new calculations of tissue-specific rates of stem cell division and cancer rates are new details in old generalizations.

Hi Raphi,The antimicrobial properties of individual phytochemicals/phytoalexins is dependent on target organism and the dynamic relative composition of a dozen different components. The purified components, as used in pharmaceuticals, have different impacts.

I don't consider any phytochemicals to be safe, because they evolved to be broadly toxic and biologically active for plant defense. They kill everything else as natural antibiotics. They even kill plants. There may be a dose or application in which they kill more baddies than goodies, but I wouldn't trust it. Babies eat breastmilk exclusively for as long as possible to protect them from the toxic phytochemicals and pregnant women are dissuaded from eating plants by morning sickness.

Monolaurin is glycerol attached to a 12-carbon fatty that is the same as in SDS, sodium dodecyl sulfate, aka sodium lauryl sulfate. SDS is used in the lab as a protein denaturant and solubilized and is an active ingredient in tooth paste. It is also the major source of canker sores, due to bits of tooth paste stuck to gums. It acts like a combination of heparin and detergent. Monolaurin is just a modified soap and should disrupt gut flora.

Ashley,Garlic supplements are silly. It is the soluble fiber that you want from garlic and not the toxic phytochemicals.

Thinking about killing off pathogenic bacteria and fungi is counterproductive. I avoid anything that claims to be antibacterial or antifungal. In almost all cases the approaches used, e.g. garlic supplements, are as damaging to gut flora as they are to any incidental pathogens. Growth of most pathogens is usually a symptom of a health problem and not the actual problem. Most of the pathogens are present, but not causing problems in healthy individuals.

Supplements are only for temporary use and should not be used daily. Feed your body and gut flora and avoid pharmaceuticals, processed foods and supplements.

ChenShak,1. Most of the other bacteria and fungi are present just because they are readily available and make the lists longer.2. I don't think it matters.3. Dairy probiotics, e.g. lactobacilli, are useful from fermented food, because they are taken daily in bulk, even though they don't contribute to the gut flora.4. Beneficial, but temporary.5. One million becomes grams to kilos in days, if there is a gut niche.

I've found your blog few month ago and it took me a couple of weeks to read and understand all the information.I had a periarteritis nodosa. Medics wanted to give me cortisone for 2 years. I refused and tried omegas3 + vit D+C.Things were better, I also removed almost sugar and starch sources. I improved a bit but dont feel cured.

I know that the next steps are the vagal nerve stimulation and the fermented veggies (book already ordered).

As you recommented it, I am eating a lot of saturated fats and I would know what are your recomandations for pre, during and post exercise that last over one hour (I like to run ultras) : proteins ? sugar with proteins ? Saturated fats ? What kind for e.g. ?

As you said that supplements are not for long term, should I stay with mine(vit c+ vit d+multivit + omega 3 + 3 probiotics + sometimes glutamine for glu repair) or can I add things like coQ10, acid alpha linoic ?

Thanks for the tip :)I have eaten raw honey (straight from the comb) before, during and after my SIBO symptoms and it did nothing for me except be delicious. SIBO symptoms are no longer an issue.

The honey idea is oversold, in part, because people confuse isolated properties of certain molecules in vitro and their potential for effectiveness in vivo, in a species specific manner. Nevertheless, it should continue to be studied IMO.

Thanks for your thoughts. I used SDS in the Vibrio fischeri gene isolating & cloning protocols this past September at Staffordshire University - fun stuff!

Its lysis capacity was precisely why it was posited as being potentially helpful.

Correct me if I'm wrong but, you seem to be saying that phytochemicals aren't specific enough to make up for their known toxicity? With that standard, couldn't that be said about most of the OTC or prescription meds? I'm all for advice on sleep, movement and nutrient dense diets before medication, but there still is a place for them when the context is right. I do not know if my context was so.

"Disrupting gut flora" is often the point though. It is analogous to hormetic stressors disrupting enzymatic activities yet, all in all, creating a favorable response at large. Surely, the potential for antimicrobials to act in a similar manner isn't out of the question, no?

Yes, I bring up the in vitro/in vivo distinction of honey because a lot of the in vivo recommendations are based on in vitro data. I don't know if that was your path to the idea of honey for SIBO but it is for many (hence why I thought it was a relevant point to make).

i've had a long-standing history of GI problems, gas, frequent stools, etc. multiple stool tests from various sources have all shown significantly elevated levels of strep bactreria (ubiome, am gut, genova), despite years of trying to feed the good guys. i'm considering a course of berberine in addition to ongoing fermented foods and probiotics to weed/feed. any thoughts on berberine when used in this fashion? thanks in advance!

You point of view on polyphenols is clear, provocative and brilliant.-Barry Sears, on his website, recently upgraded,writes-“Polyphenols have dose-dependent effects. At low doses (approximately 0.5 grams per day) they are powerful anti-oxidants and can activate gene transcription factors that increase the synthesis of additional anti-oxidative enzymes. At high levels (approximately 1.0 grams per day) polyphenols activate anti-inflammatory gene transcription factors that inhibit the initiation phase of inflammation. At still higher levels (approximately 1.5 grams per day) polyphenols activate the gene SIRT1 that increases the production of AMP kinase (AMPK) that controls cellular metabolism.”-I think Barry Sears is controversial but he is brilliant too … I would really appreciate your opinion on this …-Thank you very much doc. Ayers

kay Dee,Barry Sears is articulating conventional thinking, phenomenology, about plant polyphenols as antioxidants and manipulators of transcription. Those are just observations that ignore the structure and function of phytochemicals.

It should not be forgotten that the primary selective advantage of polyphenols in plants is disease resistance. This toxic impact on bacteria, fungi and insects results from the hydrophobic faces of the polyphenol ring structures, which permit strong bonding (10-20 kcal/mol) with the hydrophobic faces of aromatic amino acids in proteins, basic amino acids, and carbohydrates. For example, berberine binds and fluorescently labels heparin in mast cells and DNA in apoptotic blebs, while also disrupting brain amyloids.

The point is that polyphenols bind rather indescriminantly to proteins to produce physiological activity/toxicity. Most pharmaceuticals, having been derived from phytochemicals, share the same broad reactivity as their parent antibiotics, and produce many side effects, in addition to always impacting gut flora as antibiotics.

Polyphenols will interact with all proteins that interact with nucleic acids or GAGs, since these proteins bind via aromatic and basic amino acids that also bind polyphenolics. Hence, transcription factors are impacted by polyphenolics, just as topoisomerase or histones.

The graded dose impact on transcription and general impact as a mixture of polyphenols of vast diversity, speaks of broad side effects. The dubious potential benefit of turning on defenses in response to low doses of toxic polyphenols, aka hormesis, I find to be counterintuitive. It is always a sign of health to have toxins absent and defenses low. The evolutionary benefit of turning off unneeded enzymes is obvious.

Plant polyphenols are certainly natural, in the sense of natural antibiotics, but they are also always toxic. People have good detox systems to handle phytochemicals, but it is healthiest to reduce the damage of even low levels of these toxins.

I'm sure the good Doc would disagree, but there are many people and many cultures who thrive on toxins (you're from India, right?) and who believe that just because something "hurts" doesn't mean it's harmful.

Perhaps you've heard of "Yin and Yang"? The concept has to do with how apparently opposite or contrary forces are actually complementary. So, a balance of toxins and anti-inflammatory up-regulated responses, in the body, might provide a kind of homeostasis, which we see in plants who are constantly regulating their own oxidative stress.

Some people call it "Hormesis," which Doc Ayers discounts because there aren't any clinical studies that prove it exists and it's counterintuitive.

But what if hormesis does exist?

A little stress in the body can result in a significant up-regulation of immunity or anti-inflammatory responses. You see this with weight-lifting, or simple herbal medicines.

Maybe doctor Ayers is correct, that all things that "hurt" you are harmful in the long run.

But, consider that he might be wrong and avoiding the traditionally-tolerated plant toxins may actually be counterproductive to your health.

If you are healthy, your best bet may be to simply eat a traditional diet that your great-great-grandparents ate, for generations, and has been battle-tested over and over and over again, with lower chronic disease than we see here in the United States. That approach surely seems more safe than trying an extreme hypothesis, found on the Internet, that hasn't been tested by more than a handful of people.

what about Lutein in treatment of Age Related Macula Degeneration.-Lutein is in plants (not used as antibiotic/pesticide?), and the animals use it as an antioxidant vs blue rays derived free radicals ...-Make it sense lutein integration in AMD patients?

kay Dee,I don't quite understand your points. As I see it, the media view is typically that plants are natural and all natural organisms and products are good. Manmade, in contrast is dangerous. That to me is nonsense and dangerous, and I think that a closer sweeping generalization is that in the cooking pot animals are safe/ununiformly edible and healthy, and plants are relatively inedible (without the aid of gut bacteria) and toxic.

Of course there are exceptions and many animals are poisonous. Domesticated plants are much safer than their wild siblings, though they must be thoroughly detoxed by intestinal and liver enzymes to minimize damage.

Some plant toxins, such as the tetraterpenoid (8 isoprenes) carotenoids have been repurposed to protect plants from very energetic forms of chlorophyll and subsequently exploited by animals to protect retinas. But that is just expected as the exploitation of plant antibiotics to make food safer, as herbs and spices.

BTW, the Paul Jaminet article brings up a lot of good points about evolutional adaptations. Clearly, NeuGc could be a problem as well as an advantage, but the issue is about immune tolerance and not about the presence of antibodies. I think that Jaminet does not put enough weight on the consequences of damaged gut flora and related Treg deficiencies that cause problems from inadequate tolerance. NeuGc is always around and should be tolerated. Beef is not the problem, it is immunocompromised people who put themselves at risk, because of their gut dysbiosis.

I don't give much credence to molecular mimicry, but rather give aberrant self antigen presentation and tolerance defects the credit for autoimmunity.

The Traditional Dieter,Hey, I have claimed that inflammation has be cultivated to permit agriculture. Otherwise everyone would be plagued by infectious diseases.

But just because you can come up with a way of using a romantic Yin and Yang as a mechanism, doesn't mean it is consistent with simple evolutionary mechanisms. The point with the hormesis idea is that it is not observed. The molecular machinery is turned on at an evolutionarily tuned level that is incremented based on tuned responses.

If plant defenses are arbitrarily turned up to provide extra defenses against crop losses to pathogens, the impact is simply stunted yields. Defenses are expensive metabolically. The same is the detox machinery or tanning in response to sunlight.

The toxic cuisines are tolerated not because people like the taste or the stimulation, but rather because they prosper by knocking down geographically significant food contaminating microbes with appropriate plant toxins that are renamed as spices. People learn to enjoy what they must eat to survive. In most cases they trade new maladies associated with their altered food in exchange for worse. They would actually thrive without the need or use of the spicey plant toxins.

The problem with eating traditional diets out of context is that the traditional gut flora may not have migrated with the diet. That is unhealthy and extreme.

Gut flora must always be adapted to diet for health. That is the traditional approach.

Art I am a bit puzzled about some of the information that reaches us about the beneficial aspects of some of these,possibly toxic, elements. I remember an article about epigallocatechin-3-gallate in green tea and how it apparently targeted cancer cells and left healthy ones alone. I had to dig through some older files http://www.epmajournal.com/content/4/1/5 It was published in 2013. I was reminded of it this morning when Lynne McTaggart referred to it.The older folks have always known that tart cherries relieved gout issues. And many more of these. So what gives James

I think that all supplements should be used therapeutically. If you are vitamin D deficient, for example, D3 supplements as high as 10,000 IU per day may not fix the deficiency, because the problem is chronic inflammation that blocks vitamin D solar production of vitamin D.

Megadoses of D3 taken briefly can suppress chronic inflammation and permit vitamin D production in the skin to resume. Dietary sources of vitamin D are too small to be relevant and supplements of D3 can only have an impact if the skin is still producing vitamin D.

Test, supplement, then retest. Don't continue to take high doses of D3.

Some people with rosacea respond to D3 supplements with severe symptoms.

Listen to my podcast on Jimmy Moore's Livin' La Vida Low Carb Show

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About Me

I grew up in San Diego and did my PhD in Molecular, Cellular and Developmental Biology (U. Colo. Boulder). I subsequently held postdoctoral research positions at the Swedish Forest Products Research Laboratories, Stockholm, U. Missouri -Colombia and Kansas State U. I was an assistant professor in the Cell and Developmental Biology Department at Harvard University, and an associate professor and Director of the Genetic Engineering Program at Cedar Crest College in Allentown, PA. I joined the faculty at the College of Idaho in 1991 and in 1997-98 I spent a six-month sabbatical at the National University of Singapore. Most recently I have focused on the role of heparin in inflammation and disease.